Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder, affecting 1 in 1000 individuals, and results in the progressive development of renal cysts, often leading to end-stage kidney failure. 85 percent of patients with ADPKD are found to have mutations in Polycystin-1 (PC-1), a large 11-transmembrane protein with a short cytoplasmic C-terminal tail. Our lab and others have documented cleavage and nuclear translocation of this C-terminal tail (referred to as p200). A hallmark of cystic growth is increased cellular proliferation and apoptosis. Several lines of evidence indicate that PC-1 inhibits cell proliferation through regulation of the Tcf-mediated Wnt signaling pathway. Furthermore, a genetic screen for transcription factors regulated by p200 highlighted several candidates, including Ddit3, and TAZ1. Ddit3 coordinates the apoptotic response to ER stress. Inactivation of TAZ in mice results in the development of polycystic kidney disease. The signaling pathways involving each of these proteins are coordinated through the transcriptional co-activating protein p300. Taken together, these data suggest the hypothesis that p200 regulates proliferation (Tcf), apoptosis (Ddit3) and cystogensis (TAZ1) in conjunction with the transcriptial regulatory protein p300. Luciferase assays will be empolyed to measure the regulatory effects of p200 on Tcf, Ddit3 and TAZ1 signaling. Direct interactions will be assessed using immunoprecipitation experiments. Finally, an in-vitro 3D cell culture system will be used to determine the phenotypic effects of p200 on these signaling pathways. Relevance Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most cornmon life-threatening genetic disorders and, among other complications, can ultimately leads to end-stage renal failure. Currently, the only available treatments for ADPKD is are supportive, including dialysis and kidney transplant,.Transplant patients for which patientsmust often wait years on the transplant list before receiving an organ, and then must take life-long immunosuppressive medications, which carry their own health risks. Our lab is investigating the molecular defects responsible for ADPKD, and how they relate to signaling events that control cell-growth. An understanding of these mechanisms may lead to the discovery of small molecule therapies that could reduce the growth of cysts in ADPKD patients, reducing or eliminating their need for dialysis or kidney transplant and the morbidity/mortality associated with this these procedures.